DESCRIPTION (Applicant's Description) While there is persistent evidence linking electromagnetic fields (EMFs) to breast cancer, epidemiological studies thus far have not been conclusive. We suggest that this is due to inherent inadequacies in the design of those studies. The objective of this proposed research is to develop a realistic basis for the design of epidemiological studies of the relationship of EMF exposure to the incidence of human breast cancer. It is based upon the fact that human exposure to EMFs in everyday life is intermittent, and this is not reflected in the time-weighted average exposure currently the measure of dose used by epidemiologists. (This introduces a significant confounder into the study of EMFs as a link to breast cancer.) There is a body of data, in addition to our preliminary experimental results, that indicate that intermittent EM field exposures increase the magnitude of the bioresponse. Taken together these data suggest the need for a new dose-response metric. To develop such a dose-response metric, we will examine the effect of intermittent EMF exposure in an in vitro breast cancer model. These data will then form a basis for the definition of "effective dose" which can be used in epidemiological studies. A new framework for the design of dose-response exposure metrics would be established to replace the current assumption that dose is simply the product of field strength and time. With this data we can extend a kinetic model (Litovitz/Montrose) which corroborates our preliminary data that suggest that brief intermittent exposures to EM fields induce greater gene overexpression than does continuous exposure. We will interconnect the time dependence of the response and "effective" dose of continuous EM field exposure on transcript levels for the stress genes HSP27, HSP70 and HSP90, clinical markers in breast carcinoma, and the proto-oncogene c-myc in cancer and normal breast cells. All are over-expressed in mammary carcinoma and provide the critical baseline data. We will then determine the time course and "effective" dose of intermittent EM exposures as a function of time duration and field strength on transcript levels in normal and breast cancer cells for the oncogene c-myc and stress genes, and the protein products of those genes. Refractory periods that affect the return of cells to basal state after intermittent or continuous exposures should then be identifiable. These data will be used to develop a schema for describing the response to arbitrarily varying field strengths. The resultant dose-response metric would reflect the effects of environmental EMFs on breast cancer cells and, eventually, link in vitro data with the findings of realistically designed epidemiological studies.